Many conventional therapies of cancer, such as chemotherapy, radiotherapy and immunotherapy, depend to varying extents on the induction of tumor cell apoptosis. The effectiveness of apoptosis-inducing therapy can be significantly enhanced by an initial local inflammatory reaction at the tumor site and a subsequent specific immune response. Indeed, an inflammatory reaction following the induction of apoptosis has been shown to be important for the complete regression of some malignancies in rodent models. The complement system plays an important role in the inflammatory reaction and can modulate the development of both B and T cell responses. However, in the context of apoptosis, binding of natural IgM and complement activation and opsonization is critical for effective phagocytic uptake of apoptotic cells, a process considered important for limiting and resolving inflammation and for modulating immunity. We have shown that an immunotherapeutic approach involving targeted complement inhibition changes the inflammatory and immune profile within the tumor environment following radiotherapy, and significantly enhances therapeutic outcome in terms of modulating tumor growth, animal survival and induction of an anti-tumor T cell response. Our objective is to understand the mechanisms involved in this response, as well as to develop a novel strategy to enhance the therapeutic outcome of radiotherapy based on targeted complement inhibition. We hypothesize that the binding of self-reactive IgM to apoptotic tumor cells is involved in complement activation and opsonization of apoptotic cells, and that inhibiting complement-dependent apoptotic cell uptake after radiotherapy will promote necrosis, create an enhanced immuno-stimulatory environment, modulate macrophage and dendritic cell activation and differentiation, and augment or trigger specific immunity against a tumor. We will test the above hypothesis and investigate the role of IgM specificity and different complement opsonins using in vivo and in vitro therapeutic paradigms. PUBLIC HEALTH RELEVANCE: There is evidence that the outcome of apoptosis-based therapy (such as radiotherapy) is dependent to varying extents on subsequent immune reactions at the tumor site, and that the development of an anti-tumor immune response may be essential for complete eradication of disseminated disease. It is proposed to investigate a strategy and associated mechanisms for enhancing the therapeutic effect of radiotherapy, a current mainstay of cancer therapy. The approach is based on the modulation of anti-tumor immunity, and the goal is to provide an immune response that will be protective against metastasis and relapse.